Wasting (cachexia) syndrome is a cause of significant morbidity and mortality in AIDS. The purpose of this project is to define the metabolic disturbances that lead to wasting in AIDS and to determine the effect of blockade of these metabolic disturbances on energy balance in AIDS. In the previous funding period we demonstrated that subjects with AIDS and HIV infection are hypermetabolic, i.e. they have striking increases in resting energy expenditure [REE]. In addition, we have shown that both subjects with AIDS and animal models of infection have disturbances in lipid metabolism (i.e. futile cycling and inappropriate use of substrate) that could increase both REE and energy expended in meals, i.e., dietary thermogenesis [DT]. Yet while subjects with AIDS are losing weight, many of them maintain stable weight despite the presence of these metabolic disturbances. We have also found that decreases in caloric intake (CI) play a role in short-term weight loss in AIDS, however, neither the decrease in caloric intake nor the increase in REE can adequately account for the weight change weight observed in AIDS. Therefore, to understand the wasting syndrome in AIDS, one must examine these metabolic changes in the context of the whole energy balance equation. To maintain stable weight total energy expenditure [TEE] must equal caloric intake [TEE=CI] . Wasting cannot merely be predicted by the increase in REE or the decrease in CI, but rather by the mismatch of TEE and GI. Total energy expenditure = resting energy expenditure + dietary thermogenesis + energy expended in activity [EEA]. TEE = REE + DT + EEA. We hypothesize that weight is maintained in AIDS despite increased REE and perhaps DT by decreasing EEA. In addition to quantifying CI, we will directly measure TEE (using stable isotope technology), plus REE and DT (using calorimetry), then calculate EEA. Moreover, we will determine the role of altered lipid metabolism, in particular futile cycling, in producing this increased energy expenditure (REE + DT). We will then determine whether ameliorating these abnormalities in lipid metabolism by diet or drug therapy can favorably effect energy balance in AIDS. These studies could potentially lead to therapeutic interventions which could reverse or slow the wasting process in AIDS.